1. Field of the Invention
The present invention relates to an esterifying agent and its production and use. More particularly, it relates to the esterification of organic carboxylic acids, particularly complex acids of the .beta.-lactam type, by the use of methoxymethyl p-toluenesulfonate (methoxymethyl tosylate), a novel esterifying agent.
2. Description of the Prior Art
There is a growing need for esterification processes which can be applied to the manufacture of .beta.-lactam antibiotics such as the penicillins and cephalosporins. It is frequently necessary to protect carboxylic acid groups in such molecules so as to enable chemical transformations to be carried out elsewhere in the molecule. Due to the known instability of the penicillins and cephalosporins, however, it is necessary to select a carboxyl-protecting group which can be both introduced and removed under sufficiently mild conditions so as not to disrupt the sensitive .beta.-lactam ring system.
One carboxyl-protecting group which has been extensively described in the literature is the methoxymethyl ester group (--COOCH.sub.2 OCH.sub.3). This ester has been found to be generally applicable as a protecting group for the 3-carboxylic acid group of a penicillin or the 4-carboxylic acid group of a cephalosporin (see, for example, U.S. Pat. Nos. 3,996,236, 3,843,639, 4,125,716 and references cited therein).
In addition to their use as intermediates for the preparation of biologically active penicillin and cephalosporin antibiotics, the methoxymethyl esters of at least certain penicillins and cephalosporins have been reported to be useful antibiotics per se, said esters being physiologically cleaved in the body to give improved blood levels and/or different tissue distribution of antibiotic compared to the corresponding unesterified compounds [see, for example, U.S. Pat. Nos. 3,996,236 (methoxymethyl ester of hetacillin) and 4,125,716 (methoxymethyl esters of hetacephalexin and hetacefadroxil)].
Preparation of methoxymethyl esters of penicillins and cephalosporins has generally been carried out with halomethyl methyl ethers such as chloromethyl methyl ether (see, for example, U.K. Pat. No. 1,488,308). Recent severe occupational restrictions on the use of chloromethyl methyl ether [Fed. Regist. 39, 1910, 93h (Jan. 29, 1974)] due to its known carcinogenicity have produced a need for a suitable substitute for the halomethyl methyl ether reagents.
Several literature references have recently appeared describing the use of dimethoxymethane (methylal) in methoxymethylation reactions, e.g. Synthesis, August 1977, page 567; Synthesis, April 1975, page 276; Synthesis, April 1976, page 244. From the disclosed conditions and reagents required in such processes, however, it is clear that these processes are too drastic for the relatively unstable penicillin and cephalosporin molecules.
Other literature reveals the preparation (from methylal) and use of methoxymethyl methanesulfonate (J. Am. Chem. Soc., 91, 5663 (1969); U.S. Pat. No. 3,737,477). This reagent is reported to be useful as an oxyalkylating agent for ether formation. From the tremendous reactivity indicated in the J. Am. Chem. Soc. paper, it is clear that use of methoxymethyl methanesulfonate for introducing --CH.sub.2 OCH.sub.3 on a carboxylic acid group of an unstable molecule such as a penicillin or cephalosporin was not contemplated.
It was an object of the present invention to provide a new esterifying agent for methoxymethylating the 3-carboxylic acid group of a penicillin or the 4-carboxylic acid group of a cephalosporin. Another object of the invention was to provide a method for preparing methoxymethyl esters of penicillins and cephalosporins in high yield without use of a halomethyl methyl ether reagent and without destruction of the sensitive .beta.-lactam ring system. Still other objects and features of the invention will become apparent from the following description.